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Abstract

We thank Dr. Kim for her thoughtful comments1 regarding our article entitled "Usefulness
of the cytomegalovirus antigenemia assay in patients with ulcerative colitis".2 We
agree with Dr. Kim that the cytomegalovirus (CMV) antigenemia assay is not sufficient
to confirm a diagnosis of CMV colitis in patients with ulcerative colitis (UC). In
this study,2 CMV colitis (defined as the presence of inclusion bodies in H&E-stained
sections and/or positive immunohistochemical staining for CMV in the colonic mucosa)
was diagnosed in eight (66.7%) of 12 patients positive for CMV antigenemia. In contrast,
four (12.9%) of 31 patients negative for CMV antigenemia had CMV colitis. Although
positive CMV antigenemia was strongly associated with CMV colitis (P=0.001), the CMV
antigenemia assay has high specificity (87.1%) but low sensitivity (66.7%) for detecting
CMV colitis in patients with active UC. Therefore, the CMV antigenemia assay may not
be useful for the detection of CMV colitis in patients with UC due to its high false-negative
rate.
As pointed out by Dr. Kim,1 histologic evaluation including H&E staining for the presence
of cytomegalic cells and immunohistochemical staining for CMV in colonic tissues is
the gold standard for diagnosing CMV colitis.3,4 In addition, colonic tissue PCR for
CMV DNA is useful for detecting CMV infection,5 and recommended for evaluating CMV
colitis in patients refractory to immunosuppressive therapies.6 All of these methods
require colonoscopy or sigmoidoscopy in patients at high risk of developing procedure-related
complications. However, it is generally accepted that sigmoidoscopy should be considered
to assess the severity and extent of colonic inflammation as well as to define the
presence of concomitant CMV infection in all patients with active UC, except those
at high risk for perforation, such as patients with toxic megacolon.7,8
The CMV antigenemia assay detects the CMV pp65 antigen in the leukocytes of circulating
blood using fluorescent antibodies specific for pp65.3 Thus, the CMV antigenemia assay
reflects systemic CMV reactivation rather than CMV gastrointestinal disease.4 The
low sensitivity of the CMV antigenemia assay for diagnosing CMV colitis may result
from the possibility of localized CMV colonic infection without systemic CMV viremia.
The strength of the CMV antigenemia assay should be focused on systemic CMV reactivation
parameters rather than the diagnosis of CMV colitis.
Active UC patients with aggravated symptoms despite appropriate oral medication should
be hospitalized for intravenous steroid therapy.9 However, approximately 27% of the
patients require early colectomy after corticosteroid therapy.10 Thus, it is critical
to identify early predictors for steroids-refractory UC in order to facilitate the
initiation of rescue therapy and avoid colectomy. In this study, we determined that
positive CMV antigenemia was an independent predictor for steroid refractoriness in
patients with moderate-to-severe UC who required intravenous steroids. In a multicenter
cohort study, UC patients who experienced CMV reactivation showed poor clinical outcomes
in terms of colectomy and disease flare-ups.11 Therefore, patients positive for CMV
antigenemia might be at high risk for steroid refractoriness and need early ganciclovir
therapy because of systemic CMV reactivation, although whether CMV is the cause of
colitis exacerbation or plays the role of an innocent bystander in the exacerbation
of UC remains controversial.3
Considering the short processing time and high specificity for CMV colitis, the CMV
antigenemia assay is clinically useful for the early detection of CMV reactivation
in active UC patients. Therefore, we suggest that the CMV antigenemia assay might
be considered as a preliminary test for CMV reactivation and a predictor of steroid
refractoriness in all patients with moderate-to-severe UC who require systemic steroids.

Colectomy is a potentially life-saving procedure for patients with severe attacks of UC who fail medical therapy. We aimed to systematically review studies that reported the short-term colectomy rate in severe UC or reported variables that could predict treatment failure. We conducted a systematic literature search for cohort studies and controlled trials published between 1974-2006. Thirty-two studies met the inclusion criteria; 16 reported short-term outcome and predictors of therapy failure, 13 only outcome, and 3 only predictors. In the pooled analysis, 581 of 1991 patients required colectomy (weighted mean 27; 95% confidence interval [CI], 26%-28%), and 22 died (1%; 95% CI, 0.7%-1.5%). In a heterogeneity-controlled meta-regression, colectomy rate did not change during the last 30 years (R(2) = 0.07, P = .8). Cyclosporine was used in only 100 patients, with a 51% (95% CI, 41%-60%) short-term success rate. A second meta-regression failed to demonstrate a dose-colectomy response of methylprednisolone therapy beyond 60 mg daily (R(2) < 0.01, P = .98). More than 20 variables were identified in 19 studies to predict medical therapy failure, but only a few were consistently reproduced: disease extent, stool frequency, temperature, heart rate, C-reactive protein, albumin, and radiologic assessment. The short-term colectomy rate in severe UC has remained stable during the last 30 years, despite the introduction of cyclosporine, which was not used frequently. We could not find any support for administering methylprednisolone at a higher dose than 60 mg/day. Variables that predict outcome of corticosteroid therapy could aid in the development of guidelines for introduction of rescue therapies in severe UC.

The role of cytomegalovirus (CMV) in exacerbations of inflammatory bowel disease (IBD) remains a topic of ongoing debate. Current data are conflicting as to whether CMV worsens inflammation in those with severe colitis, or is merely a surrogate marker for severe disease. The interpretation of existing results is limited by mostly small, retrospective studies, with varying definitions of disease severity and CMV disease. CMV colitis is rare in patients with Crohn's disease or mild-moderate ulcerative colitis. In patients with severe and/or steroid-refractory ulcerative colitis, local reactivation of CMV can be detected in actively inflamed colonic tissue in about 30% of cases. Where comparisons between CMV+ and CMV- steroid-refractory patients can be made, most, but not all, studies show no difference in outcomes according to CMV status. Treatment with antiviral therapy has allowed some patients with severe colitis to avoid colectomy despite poor response to conventional IBD therapies. This article reviews the immunobiology of CMV disease, the evidence for CMV's role in disease severity, and discusses the outcomes with antiviral therapy.

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